Liu Xingjian, Khadtare Nikhil, Patel Hardek, Stephani Ralph, Cantor Jerome
College of Pharmacy and Health Sciences, St John's University, Queens, NY, USA.
Pulm Pharmacol Ther. 2017 Aug;45:164-169. doi: 10.1016/j.pupt.2017.06.003. Epub 2017 Jun 12.
Using a lipopolysaccharide (LPS) model of acute lung injury, we have previously shown that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a "gatekeeper" for the influx of inflammatory cells into the lung. To further investigate the potential of ET-1 to limit the progression of lung injury, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of bleomycin (BLM) or 24 h afterwards. Lung injury and repair were examined by measuring the following parameters: 1) histopathological changes; 2) neutrophil content in bronchoalveolar lavage fluid (BALF); 3) lung collagen content; 4) tumor necrosis factor receptor 1 (TNFR1) expression by BALF macrophages; 5) BALF levels of: a) transforming growth factor beta-1 (TGF-β1), b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and c) platelet-derived growth factor BB (PDGF-BB); 6) alveolar septal cell apoptosis (as measured by the TUNEL assay). For each of these parameters, animals pretreated with HJP272 showed significant reductions compared to those receiving BLM alone. In contrast, post-treatment with HJP272 was either ineffective or produced only marginally significant changes. The efficacy of a single pretreatment with HJP272 prior to induction of lung injury suggests that subsequent features of the disease are determined at a very early stage. This may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, our findings suggest that they may be useful as prophylactic agents when given in combination with drugs that have fibrogenic potential.
利用急性肺损伤的脂多糖（LPS）模型，我们先前已表明，内皮素-1（ET-1）作为一种强大的血管收缩介质，可能充当炎症细胞流入肺部的“守门人”。为了进一步研究ET-1限制肺损伤进展的潜力，在气管内注入博来霉素（BLM）前1小时或之后24小时，用内皮素受体拮抗剂（ERA）HJP272对仓鼠进行治疗。通过测量以下参数来检查肺损伤和修复情况：1）组织病理学变化；2）支气管肺泡灌洗液（BALF）中的中性粒细胞含量；3）肺胶原含量；4）BALF巨噬细胞的肿瘤坏死因子受体1（TNFR1）表达；5）BALF中以下物质的水平：a）转化生长因子β1（TGF-β1），b）基质细胞衍生因子1（通常称为CXCL12），以及c）血小板衍生生长因子BB（PDGF-BB）；6）肺泡间隔细胞凋亡（通过TUNEL检测法测量）。对于这些参数中的每一项，与仅接受BLM治疗的动物相比，用HJP272预处理的动物均显示出显著降低。相比之下，用HJP272进行治疗后要么无效，要么仅产生微小的显著变化。在诱导肺损伤之前用HJP272进行单次预处理的有效性表明，该疾病随后的特征在非常早期就已确定。这可能解释了为什么ERA对人类肺纤维化不是一种有效的治疗方法。然而，我们的研究结果表明，当与具有纤维化潜力的药物联合使用时，它们可能作为预防药物有用。
